Studies show that small variations in the CRP, FCGR2B, and ITGAM genes are associated with systemic lupus erythematosus (SLE). Mechanistic studies suggest the protein products of these genes (the blood protein C-reactive protein, the immunoreceptor Fc3RIIB, and the adhesion molecule/complement receptor integrin 1M, respectively) can interact in a tripartite fashion to modulate the activity of dendritic cells (DC), a cell type whose dysfunction can promote autoimmunity. This presents a unique opportunity to explore a gene x gene x gene model of a complex disease, i.e. does Fc3RIIB link CRP signals with ITGAM functions in SLE? Indeed, compelling in vivo data obtained from mouse models have established that (i) human CRP transgenic mice are protected from development of lupus, (ii) Fc3RIIB deficient mice are prone to developing lupus, and (iii) ITGAM deficiency hastens the onset and worsens the course of lupus in mice, and supporting in vitro data have established that (iv) CRP binds to Fc3RIIB and (v) ligation of Fc3RIIB leads to upregulation of ITGAM expression on DCs. The exceptional statistical association between CRP, FCGR2B, and ITGAM genetic variation and SLE, the provocative biology of these genes/gene products observed in mouse models, and the in vitro evidence for mechanistic interaction all point to the likelihood that CRP, Fc3RIIB, and ITGAM associate to alter the onset and/or development of autoimmunity. We hypothesize that a CRPxFCGR2BxITGAM pathway operates in vivo that dampens the activation state of DCs and fosters immune tolerance, such that inheritance of variants of one or more of these genes that perturbs this pathway increases SLE risk. In this project we will use high-throughput in vitro tests and transgenic mouse approaches to relate genetic variation in FCGR2B expression to: (i) genetic/environmental variation in blood CRP, (ii) ITGAM function, and (iii) SLE risk and causality. We have access to a large group of healthy and SLE affected people and the appropriate clinical and basic research core facilities needed to ensure that validation of this three-gene model is feasible and likely to succeed. We have assembled a unique team of investigators who will bring their combined expertise in CRP, Fc3RIIB, and ITGAM biology, inflammation and autoimmunity, and functional genomics and transgenics simultaneously to bear on the problem. Studies in the human system will investigate in vitro functional consequences of select FCGR2B variants on CRP responsiveness of DCs and their ability to effect ITGAM-mediated cellular events, and studies in the mouse system will be performed to verify the importance of human FCGR2B expression on DC mediated immune tolerance. Successful completion of our goals will add significantly to our understanding of SLE susceptibility and its clinical spectrum. PUBLIC HEALTH RELEVANCE: Each year more and more new and potentially important gene variants are discovered that are implicated in many common complex diseases, but until we understand better the function of these disease associated gene variants, and learn how they contribute to and/or cause disease, we will be unable to relate the growing genetic data to public health. In our project we hope to establish the biological cause of association of three genes (the CRP, FCGR2B, and ITGAM genes) to systemic lupus erythematosus. If we can decipher the biological reasons for the genetic evidence of association of these 3 genes to lupus, then we can better predict who might develop the disease, and better treat those that already have the disease.